Publications

Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism  (2011)

Authors:
Rossi B; Zenaro E; Angiari S; Ottoboni L; Bach S; Piccio L; Pietronigro EC; Scarpini E; Fusco M; Leon A; Constantin G
Title:
Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism
Year:
2011
Type of item:
Articolo in Rivista
Tipologia ANVUR:
Articolo su rivista
Nations of authors:
ITALIA
Language:
Inglese
Format:
Elettronico
Referee:
Name of journal:
Journal of Neuroimmunology
ISSN of journal:
0165-5728
N° Volume:
233
Number or Folder:
1-2
Page numbers:
97-105
Code PMID:
21216016
Keyword:
Cannabinoid CB1 receptor, Neuroinflammation, Lymphocyte trafficking, Integrins, Protein kinase A
Short description of contents:
It is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism.
Product ID:
58675
Handle IRIS:
11562/347453
Deposited On:
April 15, 2011
Last Modified:
November 2, 2016
Bibliographic citation:
Rossi B; Zenaro E; Angiari S; Ottoboni L; Bach S; Piccio L; Pietronigro EC; Scarpini E; Fusco M; Leon A; Constantin G, Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism «Journal of Neuroimmunology» , vol. 233 , n. 1-22011pp. 97-105

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